| First Author | Etwebi Z | Year | 2018 |
| Journal | Hypertension | Volume | 71 |
| Issue | 4 | Pages | 761-770 |
| PubMed ID | 29507101 | Mgi Jnum | J:339472 |
| Mgi Id | MGI:7522585 | Doi | 10.1161/HYPERTENSIONAHA.117.10305 |
| Citation | Etwebi Z, et al. (2018) Mechanistic Role of the Calcium-Dependent Protease Calpain in the Endothelial Dysfunction Induced by MPO (Myeloperoxidase). Hypertension 71(4):761-770 |
| abstractText | MPO (myeloperoxidase) is a peroxidase enzyme secreted by activated leukocytes that plays a pathogenic role in cardiovascular disease, mainly by initiating endothelial dysfunction. The molecular mechanisms of the endothelial damaging action of MPO remain though largely elusive. Calpain is a calcium-dependent protease expressed in the vascular wall. Activation of calpains has been implicated in inflammatory disorders of the vasculature. Using endothelial cells and genetically modified mice, this study identifies the micro-calpain isoform as novel downstream signaling target of MPO in endothelial dysfunction. Mouse lung microvascular endothelial cells were stimulated with 10 nmol/L MPO for 180 minutes. MPO denitrosylated micro-calpain C-terminus domain, and time dependently activated micro-calpain, but not the m-calpain isoform. MPO also reduced Thr(172) AMPK (AMP-activated protein kinase) and Ser(1177) eNOS (endothelial nitric oxide synthase) phosphorylation via upregulation of PP2A (protein phosphatase 2) expression. At the functional level, MPO increased endothelial VCAM-1 (vascular cell adhesion molecule 1) abundance and the adhesion of leukocytes to the mouse aorta. In MPO-treated endothelial cells, pharmacological inhibition of calpain activity attenuated expression of VCAM-1 and PP2A, and restored Thr(172) AMPK and Ser(1177) eNOS phosphorylation. Compared with wild-type mice, micro-calpain deficient mice experienced reduced leukocyte adhesion to the aortic endothelium in response to MPO. Our data first establish a role for calpain in the endothelial dysfunction and vascular inflammation of MPO. The MPO/calpain/PP2A signaling pathway may provide novel pharmacological targets for the treatment of inflammatory vascular disorders. |
